Aging is the accumulation of random damage to the building blocks of life, especially to DNA, certain proteins, carbohydrates and lipids, which begins early in life and eventually exceeds the body's self repair capabilities.
Photoaging is the complex of damages that accumulate from life-long exposure to solar ultraviolet light (UV-A and UV-B). It produces wrinkling, loss of elasticity, erythema, hyperpigmentation, and increased risk of skin cancer. UV radiation acts on the epidermis through direct exposure, and on the underlying dermis through cell-to-cell molecular signaling. Collagen fibrils in the extracellular matrix of the dermis are responsible for the strength and resiliency of the skin. Wrinkling occurs due to the loss and scarring of the dermal collagen fibrils that results from chronic exposure to solar UV.
UV irradiation leads to elevated levels of matrix metalloproteinases in human skin (MMPs). One of these enzymes, MMP-1 (also known as collagenase-1), cleaves collagen type 1, the primary constituent of the collagen fibrils in the extracellular matrix of the dermis. The imbalance of MMP-1 promotes the scarring of the collagen fibril structures. The resultant disorganization of collagen fibrils in the dermal connective tissue leads to loss of skin tone and wrinkling.
UV-A radiation has been shown to penetrate the under layers of the skin, and produce oxidative DNA damage. Following exposure of the skin to ultraviolet radiation free radicals are generated, which frequently trigger the release of inflammatory mediators. Among the inflammatory chain activities triggered by free radicals, it is known that the transcription factors NF-kB and activator protein 1 (AP-1) are activated by free radicals and pro-inflammatory cytokines, which are generated by free radical activity.
The UV-induced DNA damage also activates immunosuppressive pathways that inhibit the cutaneous immune system from reacting to challenges from the environment and tumors. The immunosuppressive cytokines TNF-Alpha and IL-10 have been observed among the repertoire of cellular responses following UV irradiation.
Irradiation by UV-A also acts to damage DNA indirectly, through the formation of oxygen radicals, to oxidize guanine to 8-oxo-guanine in nuclear and mitochondrial DNA. The oxidative events of UV-A irradiation, including metabolic stress associated with loss of mitochondrial DNA, also are associated with the inflammatory responses that lead to the release of collagen-degrading metalloproteinases into the dermal layer.
UV-B radiation, commonly referred to as the sunburn rays, is the one that cause the most concern. At the molecular lever, it is known that UV-B irradiation produces non-oxidative DNA damage, which results in DNA structural changes through dimer formation. More specifically, UV-B irradiation causes DNA damage in skin by linking adjacent bases to form cyclobutane purimidine dimer (CPD). These may be of the thymine-thymine type, or they may be between adjacent cytosines, or other combinations. CPDs are slowly removed from the DNA by a natural excision repair process, which removes about 50% of the CPDs in 24 hours. Furthermore, it is believed that a combination of UV-A and UV-B damages may be the formation of CC-TT dimer tandem doubles. These tandems may occur on the p53 tumor suppressor gene and may lead to the formation of squamous cell carcinomas. The non-oxidative DNA alteration damage is commonly assessed by quantifying the formation of TT dimers within the cells. By utilizing human living epidermal cell equivalents HaCaT Keratinocytes the amount of cyclobutyl pyrimidine TT dimers (CPD) formed can be measured.
As can be appreciated, danger occurs when DNA is damaged but not severely enough to stimulate apoptosis (natural cell death), the damaged cells then reproduce the unrepaired DNA, which initiates a continuum. The skin loses moisture and becomes dull, dry, and rough without tone and texture. Blotches, hyperpigmentation, fine lines and wrinkles develop, and then, premalignant actinic keratoses form. Finally these age spots may become malignant squamous cell carcinomas.
Various pharmaceutical or cosmetic products have been developed for treating age spots resulted from chronic UV light exposure. Most products treat age spots by bleaching, and topical color reduction by chemical reactions, however, they do not repair DNA damages, or prevent re-occurrence of skin pigmentation. On the other hand, many skin care products now include antioxidants to reduce free radicals and address oxidative damages.
Recently, Arabidopsis thaliana extract containing active component of oxoguanine glycosylase-1 has been used with liposome for restoring the DNA damaged by oxidative stress in the nucleus and in the mitochondria. However, the function of oxoguanine glycosylase-1 does not address non-oxidative DNA damages caused by UV-B.
Most recently, U.S. Patent Application Publication No. 20050226825 A1 discloses a topical composition containing water soluble extract of Uncaria species for repairing DNA damages caused by UV-B radiation by reducing dimer formation.
As can be appreciated, existing topical skin care products have limited functions in preventing and repairing DNA damages, therefore, have limited effects in preventing and restoring age related deterioration of skin conditions.
Therefore, it is desirable to have a topical composition that enables to address multiple major causes of skin aging, particularly, photoaging caused by both oxidative and non-oxidative DNA damages, and inflammatory response caused by oxidative stress.